rs930421180
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001142800.2(EYS):c.4045C>T(p.Arg1349Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,551,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001142800.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EYS | NM_001142800.2 | c.4045C>T | p.Arg1349Ter | stop_gained | 26/43 | ENST00000503581.6 | |
EYS | NM_001292009.2 | c.4045C>T | p.Arg1349Ter | stop_gained | 26/44 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.4045C>T | p.Arg1349Ter | stop_gained | 26/43 | 5 | NM_001142800.2 | A2 | |
EYS | ENST00000370621.7 | c.4045C>T | p.Arg1349Ter | stop_gained | 26/44 | 1 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152092Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000200 AC: 28AN: 1399070Hom.: 0 Cov.: 35 AF XY: 0.0000174 AC XY: 12AN XY: 690044
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152092Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74296
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 16, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 438197). This premature translational stop signal has been observed in individuals with retinitis pigmentosa (PMID: 24265693, 28041643). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg1349*) in the EYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 22, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35046417, 24265693, 28041643, 30337596, 31054281, 32581362, 31589614, 31074760, 32531858) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2017 | - - |
Retinitis pigmentosa Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 08, 2023 | Variant summary: EYS c.4045C>T (p.Arg1349X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.2e-05 in 31404 control chromosomes. c.4045C>T has been reported in the literature in mulitple individuals affected with Retinitis Pigmentosa (e.g., Weisschuh_2020). The following publication have been ascertained in the context of this evaluation (PMID: 32531858). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; and all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Retinitis pigmentosa 25 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 26, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at